Microfabricated ultrasound array for use as resonant sensors

Abstract

Apparatus and methods are provided for microfabricated sensors for use as resonant sensors. In one embodiment, an array of sensors is formed by having an electrically common membrane, an insulative spacer and a base including a driving element. Optionally, electrostatic drive forces cause the membrane to resonate, and a binding event is detected. Detection may be capacitive, piezoelectrical, piezoresistive or optical. Optional vents permit equilibration to atmosphere. Detection circuitry including phase lock loop circuitry or tunable oscillator circuitry may be utilized. High throughput screening, such as for drug discovery can be achieved.

We claim:  
     
         1 . A micromechanical sensor comprising a membrane for detecting a change in the force or membrane surface properties, said sensor comprising: 
 a substrate; and    one or more layers on or in said substrate, said one or more layers forming a cavity or said substrate and said one or more layers forming a cavity, said cavity comprising:    one or more side walls;    a membrane covering the top of said cavity, said membrane providing a substantial barrier to liquid entry through the top of said cavity; and    at least two electrodes, wherein an upper electrode is the membrane or is fabricated on, within or below the membrane and a lower electrode below the membrane, wherein said membrane composition and dimension enables said membrane to vibrate or resonate in response to changes in electrical signal in said lower electrode, and wherein said change in force or membrane surface properties are detected by the sensor as an alteration of the membrane response.    
     
     
         2 . The sensor of  claim 1 , wherein said cavity is substantially liquid free  
     
     
         3 . The sensor of  claim 1 , wherein said force is pressure.  
     
     
         4 . The sensor of  claim 1 , wherein said membrane surface property change is an increase in mass associated with the membrane.  
     
     
         5 . The sensor of  claim 4 , wherein said increase in mass results from a binding event on said membrane.  
     
     
         6 . The sensor of  claim 5 , wherein said binding event is between an analyte in solution or in a gas and a binding partner immobilized on the sensor membrane.  
     
     
         7 . The sensor of  claim 1 , wherein said substrate comprises one or more materials selected from the group consisting of; single crystal silicon, glass, gallium arsinide, silicon-on-insulator, silicon-on-sapphire, and indium phosphate.  
     
     
         8 . The sensor of  claim 1 , wherein said one or more layers comprise one or more materials selected from the group consisting of: single crystal silicon, polysilicon, silicon nitride, silicon dioxide, phosphosilicate glass, borophosphosilicate glass, aluminum nitride, zinc oxide, polyvinylidene fluoride, lead zirconate, and metal.  
     
     
         9 . The sensor of  claim 1 , wherein said one or more layers comprise materials having different electrical properties.  
     
     
         10 . The sensor of  claim 1 , wherein said substrate comprises a P-type silicon wafer having a resistance rating between 5 and 15,000Ω·cm.  
     
     
         11 . The sensor of  claim 9 , wherein said resistance rating is 10,000 Ω·cm.  
     
     
         12 . The sensor of  claim 1 , wherein said membrane is circular in shape.  
     
     
         13 . The sensor of  claim 12 , wherein said membrane has a radii of between 2.5 to 50 microns.  
     
     
         14 . The sensor of  claim 12 , wherein said membrane has a thickness of between at least 0.05 and 0.5 microns.  
     
     
         15 . The sensor of  claim 1 , wherein said membrane is polygonal in shape.  
     
     
         16 . The sensor of  claim 15 , wherein the membrane has a length of between 5 to 100 microns.  
     
     
         17 . The sensor of  claim 1 , wherein said one or more side walls have a height of between 0.1 to 2 microns.  
     
     
         18 . The sensor of  claim 1 , wherein said membrane comprises one or more of; single crystal silicon, polysilicon, silicon nitride, phosphosilicate glass, borosilcate glass, silicon dioxide, aluminum nitride, zinc oxide, polyvinylidene fluoride, lead zirconate, or metal.  
     
     
         19 . The sensor of  claim 1 , wherein said cavity has a depth of between 0.1 to 2 microns.  
     
     
         20 . The sensor of  claim 1 , wherein said cavity has a depth of between 0.3 to 1 micron.  
     
     
         21 . The sensor of  claim 1 , wherein said cavity comprises one or more vents connecting said cavity to the exterior of said sensor.  
     
     
         22 . The sensor of  claim 1 , wherein the cavity comprises one or more dielectric materials.  
     
     
         23 . The sensor of  claim 22 , wherein said dielectric materials are selected from the group consisting of; tantalum, polypropylene film, polymer-aluminum, polyester, metalized polyester, plastic foam sheet, transformer oils, paraffin, gas, argon, oxygen, and chlorine.  
     
     
         24 . The sensor of  claim 1 , wherein said cavity comprises an interior inert ambient atmosphere.  
     
     
         25 . The sensor of  claim 1 , wherein said cavity comprises a vacuum.  
     
     
         26 . The sensor of  claim 1 , wherein said two or more electrodes comprise a material selected from the group consisting of; p-doped silicon, n-doped silicon, metal alloy, titanium, gold, aluminum, and tungsten.  
     
     
         27 . The sensor of  claim 1 , wherein said upper electrode is the membrane.  
     
     
         28 . The sensor of  claim 1  wherein said two or more electrodes comprises an upper electrode and two lower electrodes, wherein one lower electrode is a actuation electrode and the other lower electrode is a detection electrode.  
     
     
         29 . The micromechanical sensor of  claim 1 , wherein said membrane comprises a binding partner that binds an analyte.  
     
     
         30 . The sensor of  claim 29 , wherein said binding partner is selected from the group consisting of; antibodies, antigens, nucleic acid molecules natural DNA, RNA, gDNA, cDNA, MRNA, tRNA, synthetic DNA, RNA, gDNA, cDNA, mRNA, tRNA, lectins, sugars, oligosaccharides, glycoproteins, receptors, growth factors, cytokines, small molecules, peptide library, natural products library, a legacy library, a combinatorial library, an oligosaccharide library, a phage display library, metabolites, drugs of abuse, metabolic by-products of drugs of abuse, enzyme substrates, enzyme inhibitors, enzyme co-factors, vitamins, lipids, steroids, metals, oxygen, gases found in physiologic fluids, cells, cellular constituents, cell membranes, associated cell structures, cell adhesion molecules, plant products, animal products, and tumor markers.  
     
     
         31 . The sensor of  claim 1 , wherein said membrane further comprises one or more piezoresistive elements, wherein said response of said membrane to said change is force or membrane surface properties is measured through a change in the resistance of said one or more piezoresistive elements.  
     
     
         32 . The sensor of  claim 1 , wherein said membrane further comprises one or more piezoelectric elements capable of producing an output voltage, and wherein said response of said membrane to said change is force or membrane surface properties is measured through a change in output current from said one or more piezoelectric elements.  
     
     
         33 . A sensor array comprising a plurality of micromechanical sensor sites, said sensor sites comprising a membrane for detecting a change in force or membrane surface properties, each sensor site comprising: 
 a substrate; and    one or more layers on or in said substrate, said one or more layers forming a cavity or said substrate and said one or more layers forming a cavity, said cavity comprising:    one or more side walls;    a membrane covering the top of said cavity, said membrane providing a substantial barrier to liquid entry through the top of said cavity; and    at least two electrodes, wherein an upper electrode is the membrane or is attached to the membrane and a lower electrode below the membrane, wherein said membrane composition and dimension enables said membrane to vibrate or resonate in response to changes in electrical current in said lower electrode, and wherein said change in force or surface membrane properties is detected by the sensor as an alteration of the membrane response.    
     
     
         34 . The sensor array of  claim 33 , wherein said cavity of each sensor is substantially liquid free.  
     
     
         35 . The sensor array of  claim 33 , wherein said force is pressure.  
     
     
         36 . The sensor array of  claim 33 , wherein said membrane surface change is an increase in mass associated with the membrane.  
     
     
         37 . The sensor array of  claim 36 , wherein said increase in mass results from a binding event on said membrane.  
     
     
         38 . The sensor array of  claim 37 , wherein said binding event is between an analyte in solution or in a gas and a binding partner immobilized on the sensor membrane.  
     
     
         39 . The sensor array of  claim 33 , wherein said substrate comprises one or more materials selected from the group consisting of; single crystal silicon, glass, gallium arsinide, silicon insulator, silicon-on-sapphire, and indium phosphate.  
     
     
         40 . The sensor of  claim 33 , wherein said one or more layers comprise one or more materials selected from the group consisting of: single crystal silicon, polysilicon, silicon nitride, silicon dioxide, phosphosilicate glass, borophosphosilicate glass, aluminum nitride, zinc oxide, polyvinylidene fluoride, lead zirconate, and metal.  
     
     
         41 . The sensor array of  claim 33 , wherein said one or more layers comprise materials having different electrical resistance properties.  
     
     
         42 . The sensor array of  claim 33 , wherein said substrate comprises a P-type silicon wafer having a resistance rating between 5 and 15,000Ω·cm.  
     
     
         43 . The sensor array of  claim 42 , wherein said resistance rating is 10,000 ΩΩ·cm.  
     
     
         44 . The sensor array of  claim 33 , wherein said membrane is circular in shape.  
     
     
         45 . The sensor array of  claim 44 , wherein said membrane has a radius of between 2.5 to 50 microns.  
     
     
         46 . The sensor array of  claim 33 , wherein said membrane has a thickness between at least 0.05 and 0.5 microns.  
     
     
         47 . The sensor array of  claim 33 , wherein said membrane is polygonal in shape.  
     
     
         48 . The sensor array of  claim 33 , wherein the membrane has a length of between 5 to 100 microns.  
     
     
         49 . The sensor array f  claim 33 , wherein said one or more side walls have a height of between 0.1 to 2 microns.  
     
     
         50 . The sensor array of  claim 33 , wherein said membrane comprises one or more of; single crystal silicon, polysilicon, silicon nitride, phosphosilicate glass, borosilcate glass, silicon dioxide, aluminum nitride, zinc oxide, polyvinylidene fluoride, lead zirconate, or metal.  
     
     
         51 . The sensor array of  claim 33 , wherein said cavity has a depth of between 0.1 to 2 microns.  
     
     
         52 . The sensor array of  claim 33 , wherein said cavity has a depth of between 0.3 to 1 micron.  
     
     
         53 . The sensor array of  claim 33 , wherein said cavity comprises one or more vents connecting said cavity to the exterior of said sensor.  
     
     
         54 . The sensor array of  claim 33 , wherein the cavity comprises one or more dielectric materials.  
     
     
         55 . The sensor array of  claim 33 , wherein said dielectric materials are selected from the group consisting of; tantalum, polypropylene film, polymer-aluminum, polyester, metalized polyester, plastic foam sheet, transformer oils, paraffin, gas, argon, oxygen, and chlorine.  
     
     
         56 . The sensor array of  claim 33 , wherein said cavity comprises an interior inert ambient atmosphere.  
     
     
         57 . The sensor array of  claim 33 , wherein said cavity comprises a vacuum.  
     
     
         58 . The sensor array of  claim 33 , wherein said two or more electrodes comprise a material selected from the group consisting of; boron, phosphorus, metal alloy, titanium and tungsten.  
     
     
         59 . The sensor array of  claim 33 , wherein said upper electrode is the membrane.  
     
     
         60 . The sensor array of  claim 33  wherein said two or more electrodes comprises an upper electrode and two lower electrodes, wherein one lower electrode is a actuation electrode and the other lower electrode is a detection electrode.  
     
     
         61 . The sensor array of  claim 33 , wherein said membrane comprises a binding partner that binds an analyte.  
     
     
         62 . The sensor array of  claim 61 , wherein said binding partner is selected from the group consisting of; antibodies, antigens, nucleic acid molecules natural DNA, RNA, gDNA, cDNA, mRNA, tRNA, synthetic DNA, RNA, gDNA, cDNA, mRNA, tRNA, lectins, sugars, oligosaccharides, glycoproteins, receptors, growth factors, cytokines, small molecules, peptide library, natural products library, a legacy library, a combinatorial library, an oligosaccharide library, a phage display library, metabolites, drugs of abuse, metabolic by-products of drugs of abuse, enzyme substrates, enzyme inhibitors, enzyme co-factors, vitamins, lipids, steroids, metals, oxygen, gases found in physiologic fluids, cells, cellular constituents, cell membranes, associated cell structures, cell adhesion molecules, plant products, animal products, and tumor markers.  
     
     
         63 . The sensor array of  claim 33 , wherein said membrane further comprises a one or more piezoresistive elements, wherein said response of said membrane to said change is force or membrane surface properties is measured through a change in the resistance of said one or more piezoresistive elements.  
     
     
         64 . The sensor array of  claim 33 , wherein said membrane further comprises one or more piezoelectric elements capable of producing an output current, and wherein said response of said membrane to said change is force or membrane surface properties is measured through a change in output voltage from said one or more piezoelectric elements.  
     
     
         65 . The sensor array of  claim 33 , further comprising one or more reference sensor sites.  
     
     
         66 . The sensor array of  claim 33 , wherein each of said sensor sites is individually addressable.  
     
     
         67 . The sensor array of  claim 33 , wherein multiple sensor sites are simultaneously addressable.  
     
     
         68 . A method for detecting the presence of an analyte suspected of being present in a sample, comprising: 
 contacting the sensor of  claim 1  with the sample and detecting a change in the membrane response, wherein said sensor membrane comprises a binding partner for the analyte.    
     
     
         69 . The method of  claim 68 , wherein said analyte and binding partner are selected from the group consisting of; ligand/receptor, antigen/antibody, enzyme/substrate, DNA/DNA, DNA/RNA, or RNA/RNA, nucleic acid/protein.  
     
     
         70 . The method of  claim 69  wherein membrane response is determined over a period of time.  
     
     
         71 . A method for detecting the presence of an analyte suspected of being present in a sample, comprising: 
 contacting the sensor array of  claim 33  with the sample and detecting a change in the membrane response of at least one sensor site, wherein said membrane of said at least one sensor site comprises a binding partner for the analyte.    
     
     
         72 . The method of  claim 71  wherein said membrane response is determined over a period of time.  
     
     
         73 . The method of  claim 71  wherein said array further comprises one or more reference sensor sites.  
     
     
         74 . A method for determining the rate of binding of a known amount of analyte in a sample to one more binding partners immobilized on separate sensor membranes of a sensor array, comprising: 
 contacting the sensor array of  claim 33  with the sample and detecting a change in the membrane response over a period of time.    
     
     
         75 . The method of  claim 74 , wherein the rate of binding correlates to the rate constant of reaction between the analyte and binding partner.  
     
     
         76 . A method for determining the rate of binding of an analyte in a sample to a plurality of binding partners each immobilized on separate sensor membranes of a sensor array, comprising: 
 contacting the sensor array of  claim 33  with the sample and detecting a change in the membrane response over a period of time.    
     
     
         77 . A method for determining the affinity between an analyte and binding partner, comprising the steps of: 
 contacting the sensor array of  claim 33  wherein said sensor array comprises one or more sensor sites each with a membrane comprising said binding partner with a sample containing a known concentration of said analyte and detecting a change in the membrane response over a period of time, 
 removing analyte bound to said sensor and repeating said contacting and detecting with a sample containing a different concentration of said analyte,  
 wherein the affinity is determined by comparing the amount of binding to the concentration of analyte in the sample.